Erythropoietin is an essential growth factor in the erythrocytic lineage. This glycoprotein hormone is secreted mainly in the kidney peritubular cells and in the fetal liver in response to hypoxia. Jelkman W, Physiol Reviews 72(2): 449 (1992). In addition, cobalt chloride also induces Epo production. Goldwasser E. et al, Blood 13: 55 (1958). Tissue hypoxia is the primary stimulus for production of erythropoietin which levels may rise to 10000 U/I plama in severe anemia as compared to the normal value of 5-20 U/I.
The injection of recombinant erythropoietin (EPO) is now widely used for long-term treatment of anemia associated with chronic renal failure, cancer and human immunodeficiency virus infections. Recombinant human erythropoietin (rhEPO) has revolutionised the treatment of anemia in patients on maintenance haemodialysis, abolishing the need for blood transfusions. Winearls CG et al., Lancet 2(8157): 1175 (1986); Gimenez LF et al., Hematology/Oncology Clinics of North America 8(5): 913 (1994).
The injection of rhEPO is widely used as a replacement therapy for anemic patients. In chronic renal failure, anemia results from a destruction of EPO-secreting cells. In chronic diseases, loss of EPO-secreting cells also occurs. Such diseases include inflammatory diseases (e.g., rheumatoid arthritis and cancers) or infectious diseases (e.g., AIDS).
Treatment is often performed as self-administered subcutaneous (s.c.) injection which is thought to be more effective than the intravenous (i.v.) route, although the bioavailability of rhEPO is low. Jensen JD et al., Eur J Clin Pharmacol 46: 333 (1994); Stockenhuber F et al., Nephron 59: 399 (1991.)
The ability to deliver this hormone by gene or cell therapy rather than by repeated injections could provide substantial clinical and economic benefits. In one embodiment we contemplate using genetically modified cells secreting high levels of human Epo.
Permanent in vivo delivery of EPO according to the devices and methods of this invention could provide great benefits in terms of cost and clinical procedures. The median weekly dose of EPO is about 150 U/kg, administered by one to three injections. The annual cost of treating a 70 kg man is about 10000 Swiss francs.
Implantation of polymer encapsulated EPO-secreting cells would abolish the need of repeated injections without affecting the biological efficacy of EPO in treatment of human hemoglobinopathies.
The cell therapy approach described here is expected to provide a convenient means for continuous delivery of EPO from a retrievable implant.